Abstract [en]

OBJECTIVE: To examine the effects of monoaminergic stabilizer (-)-OSU6162 on brain activity, as measured by blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI), in patients in the chronic phase of traumatic brain injury suffering from fatigue.

SETTING: Neurorehabilitation clinic.

PARTICIPANTS: Patients with traumatic brain injury received either placebo (n = 24) or active treatment (n = 28). Healthy controls (n = 27) went through fMRI examination at one point and were used in sensitivity analysis on normalization of BOLD response.

DESIGN: Randomized, double-blinded, placebo-controlled design.

MAIN MEASURES: Effects on BOLD signal changes from before to after treatment during performance of a fatiguing attention task.

RESULTS: The fMRI results revealed treatment effects within the right occipitotemporal cortex and the right orbitofrontal cortex. In these regions, the BOLD response was normalized relative to healthy controls at the postintervention fMRI session. No effects were seen in regions in which we previously observed activity differences between patients and healthy controls while performing this fMRI task, such as the striatum.

CONCLUSION: (-)-OSU6162 treatment had influences on functional brain activity, although the normalized regional BOLD response was observed in regions that were not a priori hypothesized to be sensitive to this particular treatment, and was not accompanied by any effects on in-scanner test performance or on fatigue.

Abstract [en]

Objectives: Rehabilitation of patients with chronic visuospatial neglect is underexplored, and little is known about neural mechanisms that can be exploited to promote recovery. In this study, we present data on resting-state functional connectivity within the dorsal attention network (DAN) in chronic neglect patients as they underwent training in a virtual reality (VR) environment that improved left-side awareness.

Methods: The study included 13 patients with visuospatial neglect persisting more than six months after a right-sided stroke. The patients underwent resting-state functional magnetic resonance imaging (fMRI). Scans were collected at baseline and after five weeks of intense training. We specifically examined resting-state functional connectivity within the DAN. In addition, using spatial concordance correlation, we compared changes in the spatial topology of the DAN with that of other networks.

Results: We found a longitudinal increase in interhemispheric functional connectivity between the right frontal eye field and the left intraparietal sulcus following training (before: 0.33 +/- 0.17 [mean +/- SD]; after: 0.45 +/- 0.13; P = 0.004). The spatial concordance analyses indicated that training influenced the DAN connectivity more than any of the other networks.

Conclusion: Intense VR training that improved left-sided awareness in chronic stroke patients also increased sporadic interhemispheric functional connectivity within the DAN. Specifically, a region responsible for saccadic eye movement to the left became more integrated with the left posterior parietal cortex. These results highlight a mechanism that should be exploited in the training of patients with chronic visuospatial neglect.

Abstract [en]

Objectives: A third of patients with stroke acquire spatial neglect associated with poor rehabilitation outcome. New effective rehabilitation interventions are needed. Scanning training combined with multisensory stimulation to enhance the rehabilitation effect is suggested. In accordance, we have designed a virtual-reality based scanning training that combines visual, audio and sensori-motor stimulation called RehAtt((R)). Effects were shown in behavioural tests and activity of daily living. Here, we use fMRI to evaluate the change in brain activity during Posners Cuing Task (attention task) after RehAtt((R)) intervention, in patients with chronic neglect.

Methods: Twelve patients (mean age=72.7years, SD=6.1) with chronic neglect (persistent symptoms >6months) performed the interventions 3 times/wk during 5weeks, in total 15hours. Training effects on brain activity were evaluated using fMRI task-evoked responses during the Posners cuing task before and after the intervention.

Results: Patients improved their performance in the Posner fMRI task. In addition, patients increased their task-evoked brain activity after the VR interventions in an extended network including pre-frontal and temporal cortex during attentional cueing, but showed no training effects during target presentations.

Conclusions: The current pilot study demonstrates that a novel multisensory VR intervention has the potential to benefit patients with chronic neglect in respect of behaviour and brain changes. Specifically, the fMRI results show that strategic processes (top-down control during attentional cuing) were enhanced by the intervention. The findings increase knowledge of the plasticity processes underlying positive rehabilitation effects from RehAtt((R)) in chronic neglect.

Main Measures: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task.

Results: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001).The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%.

Conclusion: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.

Abstract [en]

BACKGROUND: Presence of mild cognitive impairment (MCI) as a predictor for Parkinson's disease dementia (PDD) has been discussed from a clinical perspective. Recently, a Movement Disorder Society (MDS) commissioned Task Force published guidelines for PD-MCI. However, long-term follow-ups of the PD-MCI guidelines for the prediction of PDD have been sparse.

METHOD: In a community-based cohort of PD, the MDS guidelines for PD-MCI and consensus criteria for PDD were applied on 147 subjects. The predictive ability of PD-MCI for PDD was investigated. Additionally, baseline comparisons were conducted between MCI that converted to PDD and those who did not, and evolvement of motor function was investigated.

RESULTS: One fourth of the population developed PDD. MCI and age at baseline predicted later occurrence of PDD, and baseline results of tests measuring episodic memory, visuospatial function, semantic fluency, and mental flexibility differed between MCI converters and non-converters. Postural instability/gait (PIGD) phenotype and education did not predict later occurrence of PDD, but increased postural/gait disturbances were shown across time in those developing dementia.

CONCLUSION: The new PD-MCI guidelines are useful to detect patients at risk for developing PDD. The PIGD phenotype at diagnosis was not a predictor of PDD within 5 years, but the study supports a temporal association between postural/gait disturbances and PDD. Older patients with PD-MCI at baseline with decline in episodic memory, semantic fluency, and mental flexibility need to be carefully monitored regarding cognition and likely also for fall risk.

Ekman, Urban

Abstract [en]

Parkinson’s disease (PD) is next to Alzheimer’s disease (AD) the second most common neurodegenerative disease. PD has traditionally been characterised as a motor disorder, but more recent research has revealed that cognitive impairments are frequent. Cognitive impairments in executive functions, attention, and working memory with reliance on dopaminergic transmission, are often described as dominating the cognitive profile in early-phase PD. However, although knowledge about the neuropathology that underlies the cognitive impairments in PD has increased, its features are complex and knowledge remains insufficient. Therefore, the aim of the current thesis was to improve the understanding of how task-evoked brain responses relate to cognitive status in patients with PD, with and without mild cognitive impairment (MCI), and to evaluate the predictive value of PD-MCI in respect of prodromal Parkinson’s disease dementia (PDD). This was conducted within the “new Parkinsonism in Umeå” (NYPUM) project, which is a prospective cohort study. Patients with idiopathic PD were included in this thesis, and the patients were examined with a comprehensive neuropsychological battery and with a functional MRI (fMRI) working memory protocol. During scanning, patients conducted a verbal two-back task in which they needed to maintain and actively update relevant information, and the primary outcome measure was blood-oxygen-level-dependent (BOLD) signal. This thesis shows that patients with PD-MCI had significantly lower BOLD signal responses than patients without MCI in frontal (anterior cingulate cortex) and striatal (right caudate) regions (Study I). The altered BOLD response in the right caudate was associated with altered presynaptic dopamine binding. The fronto-striatal alterations persisted across time but without any additional change. However, decreased posterior cortical (right fusiform gyrus) BOLD signal responses were observed in patients with PD-MCI relative to patients without MCI across time (Study II). Finally, PD-MCI at baseline examination is highly predictive for prodromal PDD with a six-fold increased risk. Cognitive tests with a posterior cortical basis, to a greater extent, are predictive for prodromal PDD than tests with a fronto-striatal basis. The observed working memory related alterations in patients with PD-MCI suggest that early cognitive impairments in PD are linked to fronto-striatal dopaminergic dysfunction. The longitudinal development of cognitive impairment in PD reflects additional posterior cortical dysfunction. This might reflect a dual syndrome, with dopamine-depleted fronto-striatal alterations that characterise PD-MCI in general, whereas additional posterior cortical cognitive alterations with a non-dopaminergic basis to a greater extent characterise prodromal PDD. If, and how, the two potential syndromes interact, is still unclear. Thus, this thesis provides information on cognitive neuropathological changes in PD that might contribute to more relevant choices of pharmacotherapy and diagnostic accuracy in respect of PDD. However, additional large-scale longitudinal imaging studies are needed to further clarify the neuropatholgogical features of PD-MCI in respect of prodromal PDD.

Abstract [en]

Cognitive deficits are common in Parkinson's disease. Previous cross-sectional research has demonstrated a link between cognitive impairments and fronto-striatal dopaminergic dysmodulation. However, longitudinal studies that link disease progression with altered task-evoked brain activity are lacking. Therefore, our objective was to longitudinally evaluate working-memory related brain activity changes in Parkinson's disease patients with and without mild cognitive impairment (MCI). Patients were recruited within a longitudinal cohort study of incident patients with idiopathic parkinsonism. We longitudinally (at baseline examination and at 12-months follow-up) compared 28 patients with Parkinson's disease without MCI with 11 patients with Parkinson's disease and MCI. Functional MRI blood oxygen level dependent signal was measured during a verbal two-back working-memory task. Patients with MCI under-recruited bilateral medial prefrontal cortex at both time-points (main effect of group: p < 0.001, uncorrected). Critically, a significant group-by-time interaction effect (p < 0.001, uncorrected) was found in the right fusiform gyrus, indicating that working-memory related activity decreased for patients with Parkinson's disease and MCI between baseline and follow-up, while patients without MCI were stable across time-points. The functional connectivity between right fusiform gyrus and bilateral caudate nucleus was stronger for patients without MCI relative to patients with MCI. Our findings support the view that deficits in working-memory updating are related to persistent fronto-striatal under-recruitments in patients with early phase Parkinson's disease and MCI. The longitudinal evolution of MCI in Parkinson's disease translates into additional task-evoked posterior cortical changes.

Abstract [en]

Background: Many patients with Parkinson's disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinson's disease with and without MCI.

Methods: Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinson's disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umea catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at lima University. Included patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1.5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest.

Findings: Compared with controls (n=24), patients with Parkinson's disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0.001). Within the Parkinson's disease group, patients with Parkinson's disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0.005) and the bilateral anterior cingulate cortex (p<0.001) compared with patients with Parkinson's disease without MCI (n=26). In patients with Parkinson's disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinson's disease without MCI (p=0.008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0.32, p=0.031).

Interpretation: These altered brain responses in patients with Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction.